Acetylenes disubstituted with a heteroaromatic group and a 2-substituted chromanyl, thiochromanyl or 1,2,3,4-tetrahydro-quinolinyl group having retinoid-like activity

ABSTRACT

Retinoid-like activity is exhibited by compounds of the formula ##STR1## where X is S, O or NR&#39;; where R&#39; is hydrogen or lower alkyl; R 1 , R 2  and R 3  are hydrogen or lower alkyl; R 4  and R 5  are hydrogen or lower alkyl with the proviso that R 4  and R 5  cannot both be hydrogen, A is pyridazinyl, pyrimidinyl, pyrazinyl; n is 0-5, and B is H, --COOH or a pharmaceutically acceptable salt, ester or amide thereof, --CH 2  OH or an ether or ester derivative, or --CHO or an acetal derivative, or --COR 1  or a ketal derivative where R 1  is --(CH 2 ) m  CH 3  where m is 0-4, or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of application Ser. No.07/967,630, filed on Oct. 28, 1992, to be issued as U.S. Pat. No.5,272,156, which is a divisional of application Ser. No. 07/732,270,filed on Jul. 18, 1991, issued as U.S. Pat. No. 5,183,827, which is inturn a divisional of application Ser. No. 07/409,476, filed on Sep. 19,1989, issued as U.S. Pat. No. 5,045,551.

BACKGROUND

This invention relates to novel compounds having retinoid-like activity.More specifically, the invention relates to compounds having anethynylheteroaromatic acid portion and a second portion which is a2-substituted tetrahydroquinolinyl, thiochromanyl, or chromanyl group.The acid function may also be converted to an alcohol, aldehyde orketone or derivatives thereof, or may be reduced to --CH₃.

RELATED ART

Carboxylic acid derivatives useful for inhibiting the degeneration ofcartilage of the general formula4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X istetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed inEuropean Patent Application 0133795 published Jan. 9, 1985. See alsoEuropean Patent Application 176034A published Apr. 2, 1986 wheretetrahydronaphthalene compounds having an ethynylbenzoic acid group aredisclosed, and U.S. Pat. No. 4,739,098 where three olefinic units fromthe acid-containing moiety of retinoic acid are replaced by anethynylphenyl functionality.

SUMMARY OF THE INVENTION

This invention covers compounds of Formula 1 ##STR2## wherein X is S, O,or NR' where R' is hydrogen or lower alkyl; R₁ -R₃ are hydrogen or loweralkyl, R₄ and R₅ are hydrogen or lower alkyl with the proviso that R₄and R₅ cannot both be hydrogen; A is pyridinyl, thienyl, furyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is 0-5;and B is H, --COOH or a pharmaceutically acceptable salt, ester or amidethereof, --CH₂ OH or an ether or ester derivative, or --CHO or an acetalderivative, or --COR₁ or a ketal derivative where R₁ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 for treating dermatoses, such as ache, Darier's disease,psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers.These compounds are also useful in the treatment of arthritic diseasesand other immunological disorders (e.g. lupus erythematosus), inpromoting wound healing, in treating dry eye syndrome and in reversingthe effects of sun damage to skin.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 1 in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to the process for making acompound of Formula 1 which process comprises reacting a compound ofFormula 2 with a compound of Formula III in the presence of cuprousiodide and Pd(PQ₃)₂ Cl₂ (Q is phenyl) or a similar complex ##STR3##where R₁ -R₅ are the same as described above, X' is a halogen,preferably I; n, and A are the same as defined above; and B is H, or aprotected acid, alcohol, aldehyde or ketone, giving the correspondingcompound of Formula 1; or to the process of making a compound of Formula1 which consists of reacting a zinc salt of Formula 4 with a compound ofFormula 3 in the presence of Pd(PQ₃)₄ (Q is phenyl) or a similarcomplex. ##STR4## where R₁ -R₅, and X, are the same as defined above,giving the corresponding compound of Formula 1; or homologating acompound of the Formula 5 ##STR5## where n is 0-4 to give an acid ofFormula 1; or

converting an acid of Formula 1 to a salt; or

forming an acid addition salt;

converting an acid of Formula 1 to an ester; or

converting an acid of Formula 1 to an amide; or

reducing an acid of Formula 1 to an alcohol or aldehyde; or

converting an alcohol of Formula 1 to an ether or ester; or

oxidizing an alcohol of Formula 1 to an aldehyde; or

converting an aldehyde of Formula 1 to an acetal; or

converting a ketone of Formula 1 to a ketal.

GENERAL EMBODIMENTS Definitions

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where B (of Formula 1) is --COOH, this term covers theproducts derived from treatment of this function with alcohols. Wherethe ester is derived from compounds where B is --CH₂ OH, this termcovers compounds of the formula --CH₂ OOCR where R is any substituted orunsubstituted aliphatic, aromatic or aliphatic-aromatic group.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids oralcohols. Here, and where ever else used, lower alkyl means having 1-6carbon atoms. Also preferred are the phenyl or lower alkylphenyl esters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono-and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals include the radicals of the formula --CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₁ O-- where R₁ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound ofthis invention having a functionality capable of forming such salt, forexample an acid or an amine functionality. A pharmaceutically acceptablesalt may be any salt which retains the activity of the parent compoundand does not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The preferred compounds of this invention are those where the ethynylgroup and the B group are attached to the 2 and 5 positions respectivelyof a pyridine ring (the 6 and 3 positions in the nicotinic acidnomenclature being equivalent to the 2/5 designation in the pyridinenomenclature) or the 5 and 2 positions respectively of a thiophene grouprespectively; n is O; and B is --COOH, an alkali metal salt or organicamine salt, or a lower alkyl ester, or --CH₂ OH and the lower alkylesters and ethers thereof, or --CHO and acetal derivaives thereof. Themore preferred compounds shown in Formula 6 are:

ethyl 6-[(2,2,4,4-tetramethylthiochroman-6-yl)-ethynyl] nicotinate(Compound I, X=S, R_(3=H), R"=C₂ H₅)

6-[(2,2,4,4-tetramethylthiochroman-6-yl)-ethynyl] nicotinic acid(Compound 2, X=S, R₃ =H)

ethyl 6-[(2,2,4,4-tetramethylchroman-6-yl)-ethynyl] nicotinate (Compound3, X=O, R₃ =H, R"=C₂ H₅)

6-[(2,2,4,4-tetramethylchroman-6-yl)-ethynyl] nicotinic acid (Compound4, X=O, R₃ =H, R"=H)

ethyl 6-[(2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl] nicotinate(Compound 5, X=S, R₃ =CH₃, R"=C₂ H₅)

6-[(2,2,4,4,7-pentamethylthiochroman-6-yl)-ethynyl] nicotinic acid(Compound 6, X=S, R₃ =CH₃, R"=H)

ethyl 6-[(2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl] nicotinate(Compound 7, X=O, R₃ =CH₃, R"=C₂ H₃)

6-[(2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl] nicotinic acid (Compound8, X=O, R₃ =CH₃, R"=H) ##STR6##

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and similar considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne, oral administration may also be used. Any commontopical formulation such as a solution, suspension, gel, ointment, orsalve and the like may be used. Preparation of such topical formulationsare well described in the art of pharmaceutical formulations asexemplified, for example, Remington's Pharmaceutical Science, Edition17, Mack Publishing Company, Easton, Pa. For topical application, thesecompounds could also be administered as a powder or spray, particularlyin aerosol form.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or intermuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the drugpotentially could be used in a prophylactic manner to prevent onset of aparticular condition. A given therapeutic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, a given therapeutic concentration will bebest determined at the time and place through routine experimentation.However, it is anticipated that in the treatment of, for example, ache,or other such dermatoses, that a formulation containing between 0.001and 5 percent by weight, preferably about 0.01 to 1% will usuallyconstitute a therapeutically effective concentration. If administeredsystemically, an amount between 0.01 and 100 mg per kg body weight perday, but preferably about 0.1 to 10 mg/kg, will effect a therapeuticresult in most instances.

The retionic acid like activity of these compounds was confirmed throughthe classic measure of retionic acid activity involving the effects ofretionic acid on ornithine decarboxylase. The original work on thecorrelation between retionic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcauses for ODC activity increase are unknown, it is known that12-O-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retionic acid inhibits this induction of ODC activity by TPA. Thecompounds of this invention also inhibit TPA induction of ODC asdemonstrated by an assay essentially following the procedure set out inCancer Res., 35: 1662-1670, 1975.

By way of example of retinoic acid-like activity it is noted that in theassay conducted essentially in accordance with the method of Verma &Boutwell, ibid, the following examples of the preferred compounds of thepresent invention (Compounds 1, 3 and 7) attained an 80% inhibition ofTPA induced ODC activity at the following concentrations (IC₈₀):

    ______________________________________                                        Compound      IC.sub.80 conc (nmols)                                          ______________________________________                                        1             0.69                                                            3             0.13                                                            7             0.2                                                             ______________________________________                                    

SPECIFIC EMBODIMENTS

The compounds of this invention can be made by a number of differentsynthetic chemical pathways. To illustrate this invention, there is hereoutlined a series of steps which have been proven to provide thecompounds of formula 1 when such synthesis is followed in fact and inspirit. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by Formula 1.Furthermore, the synthetic chemist will readily appreciate that theherein described synthetic steps may be varied and or adjusted by thoseskilled in the art without departing from the scope and spirit of theinvention.

Compounds of Formula 1 where X is --S-- and R₄ and R₅ are hydrogen orlower alkyl, with the proviso that R₄ and R₅ both are not hydrogen, areprepared as per Reaction Scheme I ##STR7##

In Reaction Scheme I, R₁ -R₃ are hydrogen or a lower alkyl group, A isas defined above in connection with Formula 1, n is 0-5 and B is H, or aprotected acid, alcohol, aldehyde or ketone. X' is Cl, Br or I when n isO but preferably be Br or I when n is 1-5.

Compounds of Formula 1 where X is oxygen and R₄ and R₅ are hydrogen orlower alkyl, with the proviso that R₄ and R₅ both are not hydrogen, areprepared as per Reaction Scheme 2. ##STR8##

In Reaction Scheme 2 the definitions of R₁ -R₅, n, A, B and X' are thesame as in Reaction Scheme 1.

A general description of the synthetic steps outlined in ReactionSchemes 1 and 2 is as follows.

In Reaction Scheme 1 the 4-bromo-thio-phenol (Compound 9) is acylatedwith an acylating agent, such as an acid chloride (Compound 10) derivedfrom an appropriately substituted acrylic acid. The acylation isconducted in an inert solvent (such as tetrahydrofuran) in the presenceof strong base (for example sodium hydrdride). The resulting thioesters(Compound 11) which contains the olefinic bond of the acrylic acidmoiety is ring closed in the presence of a Fridel Crafts type catalyst(such as aluminum chloride) by stirring in a suitable solvent such asmethylene chloride. The resulting 2-oxo-6-bromo-thiochromane (Compound12) is usually isolated in crystalline form.

The R₄ and/or R₅ substituents (both of which cannot be hydrogen inaccordance with the invention) and which preferably are identical withone another (for example both are methyl) are introduced by treating the2-oxo-6-bromo-thiochroman (Compound 12) with a Grignard reagent, bearingthe alkyl substituents R₄ and R₅ (such as methylmagnesium bromide whenR₄ and R₅ are methyl). It will be readily understood by those skilled inthe art that depending on the relative molecular ratios of the Grignardreagent and of the oxo-thiochroman compound (Compound 12), and alsodepending on the reaction conditions, the primary products of thereaction may be derivatives where either one or two alkyl groups havebeen introduced through the Grignard reaction. When the Grignard reagent(such as methylmagnesium bromide) is in excess, the thiochroman ring isopened and the tertiary alcohol derivative of the 4-bromo thiophenol(Compound 13) is formed.

Ring closure of the thiophenol derivative (Compound 13) which has thedesired R₁, R₂, R₃, R₄ and R₅ substituents, is affected by heating inacidic conditions, preferably by heating Compound 13 in aqueous acid.The resulting 6-bromothiochroman which bears the desired alkyl (orhydrogen) substituents, R₁, R₂, R₃, R₄ and R₅ is shown as Compound 14 inReaction Scheme 1.

To introduce the acetylene (ethyne) portion into the molecule, thesubstituted 6-bromothiochroman 14 is reacted withtrimethylsilylacetylene in the presence of cuprous iodide and a suitablecatalyst, typically having the formula Pd(PQ₃)₂ Cl₂ (Q is phenyl). Thereaction is typically conducted in the presence ofbis(triphenylphosphine) palladium (II) chloride catalyst, an acidacceptor, (such as triethylamine) under an inert gas (argon) atmosphere,by heating in a sealed tube.. The resulting6-trimethylsilylethynylthiochroman, is shown as Compound 15 in ReactionScheme 1.

As is shown on Reaction Scheme 1, the trimethylsilyl moiety is removedfrom the 6-trimethylsilylethynyl-thiochroman 15 in the next syntheticstep, to provide the ring substituted 6-ethynyl-thiochroman derivative(Compound 16). The latter reaction is conducted under basic conditions,preferably under an inert gas atmosphere.

In order to introduce the heteroaryl substituent on the acetylene(ethyne) portion of Compound 16, Compound 16 is coupled with the reagentX'--A--(CH₂)_(n) --B (Formula 3) where the symbols X', A and B have thesame meaning as defined in connection with Formula 3. In other words,the heteroaryl substituent is introduced into the 6-thiochromanylethyne16 by reacting the latter with a halogen substituted heteroaromaticcompound (Formula 3) in which the heteroaramatic nucleus (A) either hasthe desired substituent [(CH₂)_(n) --B] or wherein the actualsubstituent (CH₂)_(n) --B can be readily converted to the desiredsubstituent by means of organic reactions well known in the art.

Coupling of the 6-thiochromanylethyne 16 with the reagentX'--A--(CH₂)_(n) --B is affected directly in the presence of cuprousiodide, a suitable catalyst, typically of the formula Pd(PQ₃)₂ Cl₂ andan acid acceptor., such as triethylamine, by heating in a sealed tubeunder an inert gas (argon) atmosphere.

The resulting disubstituted acetylene compound (Compound 18) may be thetarget compound made in accordance with the invention, or maybe readilyconverted into the target compound by such steps as salt formation,esterification, deesterification, homologation, amide formation and thelike. These steps are further discussed below.

Compound 18 may also be obtained by first converting the6-thiochromanylethyne derivative 16 into the corresponding metal salt,such as a zinc salt, (Compound 17) and thereafter coupling the salt 17with the reagent X'--A--(CH₂)_(n) --B (Formula 3) in the presence of acatalyst having the formula Pd(PQ₃)₄ (Q is phenyl), or similar complex.

Derivatization of Compound 18 is indicated in Reaction Scheme 1 asconversion to "homologs and derivatives", Compounds 19.

More specifically with respect to either derivatization or deblocking ofprotected functionalities in Compound 18, or with respect to thepreparation of heteroarometic compounds of the formula X'--A--(CH₂)_(n)--B, (which after coupling either directly yield the compounds of theinvention, or are readily converted into them) the following is noted.

Where a protected heteroaromatic compound is needed to couple with thecompounds of Formula 2 (Compounds 16 in Reaction Scheme 1), such may beprepared from their corresponding acids, alcohols, ketones or aldehydes.These starting materials, the protected acids, alcohols, aldehydes orketones, are all available from chemical manufacturers or can beprepared by published methods. Carboxylic acids are typically esterifiedby refluxing the acid in a solution of the appropriate alcohol in thepresence of an acid catalyst such as hydrogen chloride or thionylchloride. Alternatively, the carboxylic acid can be condensed with theappropriate alcohol in the presence of dicyclohexylcarbodiimide anddimethylaminopyridine. The ester is recovered and purified byconventional means. Acetals and ketals are readily made by the methoddescribed in March, "Advanced Organic Chemistry," 2nd Edition,McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones allmay be protected by forming respectively, ethers and esters, acetals orketals by known methods such as those described in McOmie, PlenumPublishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley &Sons, 1981.

To increase the value of n before effecting a coupling reaction, wheresuch compounds are not available from a commercial source, theheteroaromatics where B is --COOH are subjected to homologation bysuccessive treatment under Arndt-Eistert conditions or otherhomologation procedures. Alternatively, heteroaromatics where B is adifferent from COOH, may also be homologated by appropriate procedures.The homologated acids can then be esterified by the general procedureoutlined in the preceding paragraph.

An alternative means for making compounds where n is 1-5 is to subjectthe compounds of Formula 1, where B is an acid or other function, tohomologation, using the Arndt-Eistert method referred to above, or otherhomologation procedures.

The acids and'salts derived from Formula 1 are readily obtainable fromthe corresponding esters. Basic saponification with an alkali metal basewill provide the acid. For example, an ester of Formula 1 may bedissolved in a polar solvent such as an alkanol, preferably under aninert atmosphere at room temperature, with about a three molar excess ofbase, for example, potassium hydroxide. The solution is stirred for anextended period of time, between 15 and 20 hours, cooled, acidified andthe hydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about -10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert inorganicsolvent such as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alky halides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexlcarbodiimide and dimethlaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds where B is H can be prepared from the correspondinghalo-heterocyclic entity, preferably where the halogen is I.

With reference to Reaction Scheme 2, phenol, or a phenol substituted inthe 3 (meta) position by an alkyl substituent (R₃) (Compound 20) isacylated with an acylating agent, such as an acid chloride (Compound 10)derived from an appropriately substituted acrylic acid. In ReactionScheme 2, just as in Reaction Scheme 1, the R₁ and R₂ substituents ofthe target compounds are introduced through this acrylic acid derivative10. The acylation with the acid chloride 10 is preferably conducted inthe presence of a strong base (e.g. sodium hydride) in an inert solvent(such as tetrahydrofuran). The resulting substituted phenyl-acrylate isshown in Reaction Scheme 2 as Compound 21.

The substituted phenyl-acrylate 21 is ring closed under Friedel Craftstype reaction conditions (AlCl₃ catalyst, in an inert solvent, such asmethylene chloride) to provide the 2-oxo-chroman compound (Compound 22)which bears, in the 4-position, the R₁ and R₂ substituents and in the6-position the R₃ substituent (as applicable). Just like the analogous2-oxo-thiochroman 12 in Reaction Scheme 1, the 2-oxo-chroman 22 ofReaction Scheme 2 is treated with a Grignard reagent to introduce the R₄and R₅ substituents. As it was noted out above, R₄ and R₅ both cannot behydrogen, and in the preferred embodiments R₄ and R₅ are identical, forexample both are methyl or ethyl. When R₄ and R₅ are methyl, theGrignard reagent is preferably methylmagnesium chloride (dissolved intetrahydrofuran, THF). A solution of Compound 22 in a suitable solvent,for example in dry diethylether is added to this Grignard reagent. Theresulting phenol containing a tertiary alcohol side chain, (that is amolecule in which the chroman ring had been opened) is shown in ReactionScheme 2 as Compound 23.

Compound 23 which already has the desired R₁, R₂, R₃, R₄ and R₅substituents, is ring closed under acidic conditions, (e.g. by heatingin aqueous sulfuric acid) to provide the chromane derivative (Compound24). It should be noted that up to this point in the synthetic sequence(which is preferably but not necessarily exclusively used for making thecompounds of the invention) similar or analogous steps are involved formaking both the thiochroman (Reaction scheme 1) and chroman derivatives(Reaction Scheme 2), the only difference being that in Reaction Scheme 2the starting phenol derivative does not have a halogen (such as a bromo)substituent.

Because of the lack of the halogen substituent in the preferredsynthetic sequence for preparing the chroman compounds of the invention,the preferred and herein illustrated steps (Reaction Scheme 2) forintroducing the acetylene (ethyne) group into the 6-position of thechroman moiety are different from the steps utilized for introducing theacetylene moiety into the analogous thiochroman (Reaction Scheme 1).

Thus, in Reaction Scheme 2 an acetyl group is introduced into the6-position of the chroman derivative 24 under Friedel Crafts typeconditions. This acetylation is preferably conducted with acetylchloride, in nitromethane solvent, in the presence of aluminum chloride.The resulting 6-acetyl-chroman derivative is Compound 25.

The acetylenic (triple) bond is introduced into the molecule byconverting the 6-acetyl moiety of chroman 25 to an acetylene moiety.This is accomplished, preferably, by treatment with lithiumdiisopropylamide (at low temperature, such as -78 degrees C.) whichcauses enolization of the acetyl group. The intermediate enol compound(not shown in Reaction Scheme 2) is esterified by treatment-withdiethylchlorophosphate (or the like) and is again reacted at reducedtemperature (e.g. -78 degrees C.) with lithium diisopropylamide, to formthe triple bond (presumably by an elimination reaction) and to yield the6-ethynyl-chroman derivative (Compound 26).

It is noted at this point that the present invention is not intended tobe limited or bound by the above-mentioned and other theories ofreaction mechanisms. Brief description of theory of reaction mechanisms(where applicable) are given to further enable and facilitate the workof a skilled artisan in the field to modify and adjust the syntheticconditions to fit particular specific intermediates and to make theseveral compounds of the invention, without departing from the scope andspirit of the invention.

Referring back again to Reaction Scheme 2, the 6-ethynylchromanderivative 26 may be converted into the target compounds of theinvention in synthetic steps which are analogous to the conversion of6-ethynyl-thiochromans (Compound 16) into the corresponding targetthiochroman derivatives (See Reaction Scheme 1). Briefly, Compound 26 ispreferably heated with a reagent X'--A--(CH₂)_(n) --B (Formula 3) in thepresence of cuprous iodide, a suitable catalyst, typically of theformula Pd(PQ₃)₂ Cl₂ (Q is phenyl or the like) and an acid acceptor,such as triethylamine. This coupling reaction, yields the target chromancompounds, (Compound 28) or such derivatives which are readily convertedinto the target compounds by protection, deprotection, esterification,homologation etc., as is discussed in connectin with Reaction Scheme 1.The homologs are indicated, as a group, as Compound 28a in ReactionScheme 2.

Alternatively, the 6-ethynyl-chroman compounds 26 may first be convertedto the corresponding metal (zinc) salt (Compound 27) and thereaftercoupled with the reagent X'--A--(CH₂)_(n) --B (Formula 3) underconditions which are similar to the conditions described in ReactionScheme I for coupling of Compounds 18 with the same reagent.

The compounds of the invention where X=NR¹ (R¹ is H or lower alkyl) canbe made, for example, in a synthetic sequence which is analogous to thesequences described in the sequences described in Reaction Schemes 1 and2, but starting with an appropriately substituted aniline derivativeinstead of a thiophenol or phenol.

The following examples of specific compounds of the invention, andspecific examples of the synthetic steps in which the compounds andcertain intermediates are made, are set out to illustrate the invention,not to limit its scope.

SPECIFIC EXAMPLES Ethyl 6-chloronicotinate (Compound 29)

A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol)ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 gdimethylaminopyridine in 200 ml methylene chloride was heated at refluxfor 2 hours. The mixture was allowed to cool, solvent removed in vacuoand residue subjected to flash chromatography to give the title compoundas a low-melting white solid. PMR (CDCl₃): & 1.44 (3H, t, J-6.2 Hz) 4.44(2H, q, J-4.4 Hz), 7.44 (1H, d, J-8.1 Hz), 8.27 (1H, dd, J-8.1 Hz, 3Hz), 9.02 (1H, d, J-3 Hz).

The foregoing procedure may be used to esterify any of the otherhalo-substituted acids employed in the making of these compounds suchas:

ethyl 2-(2-chloropyrid-5-yl)acetate;

ethyl 5-(2-chloropyrid-5-yl)pentanoate;

ethyl 2-(2-iodofur-5-yl)acetate;

ethyl 5-(2-iodofur-5-yl)pentanoate;

ethyl 2-(2-iodothien-5-yl)acetate;

ethyl 5-(2-iodothien-5-yl)pentanoate;

ethyl 2-(3-chloropyridazin-6-yl)acetate;

ethyl 5-(3-chloropyridazin-6-yl)pentanoate;

and the corresponding chloro, or other halo, substituted pyrimidinyl orpyrazinyl analogues of such esters. The just mentioned esters (includingethyl-6-chloronicotinate, Compound 29) can serve as the reagents, X¹--A--(CH₂)_(n) --B for coupling with the corresponding ethynyl compounds(such as Compounds 16 and 26, or their zinc salts 17 and 27) to providethe target compounds of the invention.

S-(4-bromopenyl) 3,3-dimethylthioarylate (Compound 30)

To an ice bath cooled solution of 1.92 g (80 mmol) of NaH (obtained froma 60% suspension in mineral oil by 3×15 ml hexane wash) in 30 ml of dryTHF was added slowly under argon a solution of 15.1 g (80 mmol) of4-bromothiophenol in 60 ml of dry THF over 1 h. The mixture was stirredat 0 degrees C. for a further 30 min and then treated with a solution of10.1 g (85 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. Thecooling bath was then removed and the mixture then stirred at roomtemperature for 40 h. The reaction mixture was poured into 200 ml ofwater containing 2 ml of glacial acetic acid and the organic layer wasseparated. The organic layer was washed with 2×75 ml of water and thendried (MgSO₄). The solvent was removed in vacuo to give the titlecompound as a yellow oil. PMR (CDCl₃): & 1.91 (3H, s), 2.14 (3H, s),6.03-6.06 (1H, m), 7.28 (2H, d, J-8.6 Hz), 7.53 (2H, d, J-8.6 Hz).

4,4-Dimethyl-6-bromo-2-oxo-thiochroman (Compound 31)

To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminumchloride in 140 ml of methylene chloride was added under nitrogen asolution of 21.64 g (79.9 mmol) of S-(4-bromophenyl)3,3-dimethyl-thioacrylate (Compound 30) in 100 ml of methylene chloride.The mixture was then stirred at room temperature for 72 h and thenpoured into 250 g of an ice and brine mixture. The mixture was extractedwith methylene chloride and the combined organic extracts were washedwith saturated NaCl solution and then dried (MgSO₄). The solvent wasremoved in vacuo and the residue recrystallized from hexanes to give thetitle compound as white crystals. PMR (CDCl₃): & 1.40 (6H, s), 2.67 (2H,s), 7.31-7.40 (3H, m). MS exact mass, m/e 269.9714 (calcd. for C₁₁ H₁₁SOBr, 269.9714).

4-Bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 32)

To 3.49 g (32.8 mmol) of lithium perchlorate was added under argon 35 mlof 3.0M (105 mmol) methyl magnesium bromide in ether. The above mixturewas treated dropwise with stirring with a solution of 2.961 g (10,926mmol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman (Compound 31) and thereaction mixture was then heated at reflux for 70 h. The reactionmixture was then allowed to cool and poured onto a mixture of 100 g ofice and 8 ml of conc. H₂ SO₄. The organic layer was separated and theaqueous layer was extracted with 2×25 ml of ether. The organic layerswere combined and washed successively with 2×25 ml of saturated NaHCO₃solution, 25 ml of water and 25 ml of saturated NaCl solution and thendried (MgSO₄). The solvent was removed in-vacuo and the residue purifiedby flash chromatography to give the title compound as a pale yellow oil.PMR (CDCl₃): & 1.05 (6H, s), 1.52 (6H, s), 2.30 (2H, s), 3.71 (1H, s),7.22 (1H, dd, J-8.5 Hz, 2.1 Hz), 7.28 (1H, d, J-8.5 Hz), 7.35 (1H, d,J-2.1 Hz)

Using ethyl magnesium bromide, instead of methyl magnesium bromide,provides the corresponding 4-bromo-2- (1,1 dimethyl3-ethyl-3-hydroxypentyl)-thiophenol.

2,2,4,4-Tetramethyl-6-bromothiochroman (Compound 33)

A mixture of 500 mg (1.49 mmol) of4-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 32) and8 ml of 20 percent aqueous H₂ SO₄ was heated at reflux for 24 h. Themixture was extracted with hexanes, the organic extracts were combinedand washed successively with water, saturated NaHCO₃, water again,saturated NaCl and then dried (MgSO₄). The solvent was removed in vacuoand the residue purified by flash chromatography (silica; hexanes) togive the title compound as a colorless oil. PMR (CDCl₃): & 1.35 (6H, s),1.40 (6H, s), 1.93 (2H, s), 7.17 (1H, dd, J-8.4 Hz, 2.1 Hz), 7.23 (1H,d, J-8.4 Hz), 7.26 (1H, d, J-2.1 Hz). MS exact mass, m/e 284..0221(calcd. for C₁₃ H₁₇ S Br, 284.0234).

2,2,4,4-Tetramethyl-6-trimethylsilylethynyl-thiochroman (Compound 34)

A solution of 600 mg (2.11 mmol) of2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml oftriethylamine was placed in a heavy-walled tube and degassed and thentreated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetyleneand a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg(0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. Thereaction mixture was degassed again, then placed under argon and thetube was sealed. The mixture was heated at 100 degrees C. for 24 h,allowed to cool to room temperature and then treated with a further 1.4g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg(0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) ofbis(triphenylphosphine) palladium (II) chloride. The mixture was thendegassed, placed under argon and then heated in the sealed tube at 100degrees C. for 96 h. The mixture was cooled to room temperature andextracted with 3×10 ml of ether. The organic extracts were combined,washed successively with 25 ml of water and 25 ml of saturated sodiumchloride solution and then dried (MgSO₄). The solvent was removed invacuo and the residue purified by flash chromatography (silica; hexanesfollowed by 3% ethyl acetate in hexanes) to give the title compound as ayellow, crystalline solid. PMR (CDCl₃): & 0.23 (9H, s), 1.36 (6H, s),1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J-8.2 Hz, 1.8 Hz), 7.25 (1H,d, J-1.8 Hz), 7.30 (1H, d, J-8.2 Hz). MS exact mass, m/l 302.1519(calcd. for C₁₈ H₂₆ S Si, 382.1524).

2,2,4,4-Tetramethyl-6-ethynylthiochroman (Compound 35)

To a solution of 527.6 mg (1.75 mmol) of2,2,4,4-tetramethyl-6-trimethylsilyl-ethynylthiochroman (Compound 34) in4 ml of isopropanol was added, under argon, 4 ml of 1N KOH solution. Thereaction mixture was stirred at room temperature for 20 h and theisopropanol was then removed under vacuum. The residue was extractedwith ether and the combined ether extracts were washed successively withwater and saturated NaCl solution and then dried (MgSO₄). The solventwas removed in vacuo to give the title compound as a yellow oil. PMR(CDCl₃): & 1.34 (6H, s), 1.37 (6H, s), 1.91 (2H, s), 2.99 (1H, s), 7.17(1H, dd, J-8.1 Hz, 1.8 Hz), 7.26 (1H, d, J-1.8 Hz), 7.30 (1H, d, J-8.1Hz). MS exact mass, m/e 230.1122 (calcd. for C₁₅ H₁₈ S, 230.1129)

Ethyl 6-[(2,2,4,4-tetramethyl-thiochroman-6-yl)ethynyl]nicotinate(Compound 1)

A solution of 232 mg (1.01 mmol) of2,2,4,4-tetramethyl-6-ethynylthiochroman (Compound 35) and 190 mg (1.03mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml oftriethylamine was placed in a heavy-walled glass tube, degassed, placedunder argon and then treated with a powdered mixture of 53 mg (0.28mmol) of cuprous iodide and 84 mg (0.12 mmol) of bis(triphenylphosphine)palladium (II) chloride. The mixture was degassed again, placed underargon and the tube was sealed. The reaction mixture was heated at 55degrees C. for 60 h and then cooled to room temperature. The mixture wastreated with water and ether and the organic layer was separated. Theaqueous layer was extracted with ether, the organic layers were thencombined and washed with saturated NaCl solution and then dried (MgSO₄).The solvent was removed in vacuo and the resultant residue was purifiedby flash chromatograhy (silica; 10% ethyl acetate in hexanes) to givethe title compound as a dark yellow oil. PMR (CDCl₃): & 1.32-1.43 (15H,m), 1.92 (2H, s), 4.38 (2H, q, J-7.1 Hz), 7.28 (1H, dd, J-8.3 Hz, 1.8Hz), 7.32-7.38 (2H, m), 7.53 (1H, d, J-8.3 Hz), 8.24 (1H, dd, J-8.2 Hz,2.2 Hz), 9.16 (1H, d, J-2.2 Hz). MS exact mass, m/e 379.1594 (calcd. forC₂₃ H₂₅ NO₂ S, 379.1606).

Using the method for the preparation of Compound 1, but substituting theappropriate ethynylthiochroman (Compound 16 in Reaction Scheme 1) andthe appropriate halo substituted heteroaromatic ester (Formula 3,prepared for example as specifically described for Compound 29) thefollowing compounds of the invention may be prepared:

ethyl 6-[(2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl]nicotinate;

ethyl6-[(2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl]nicotinate;

ethyl6-[(2,2,4,4-tetramethyl-7-propylthiochroman-6-yl)ethynyl]nicotinate;

ethyl6-[(2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl]nicotinate;

ethyl [((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl[((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl[((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl[((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl3-[((2,2,4,4-tetramethylthiochroman-2-yl)ethynyl)pyrid-5-yl]propionate;

ethyl3-[((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrid-5-yl]propionate;

ethyl3-[((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrid-5-yl]propionate;

ethyl3-[(2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyrid-5-yl]propionate;

ethyl5-[((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl5-[((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl5-[((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl [5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)fur-2-yl]acetate;

ethyl[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)fur-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)fur-2-yl]acetate;

ethyl [5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)fur-2-yl]acetate;

ethyl5-[-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl5-[5((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl[5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl5-[5-2,2,4,4-tetramethylthiochroman-6-yl)-ethynyl)thien-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)thien-2-yl]pentanoate

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)thien-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)thien-2-yl]pentanoate;

ethyl[6-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl[6((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl[6-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl[6-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl-5-[6((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl5-[6-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl5-[6-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl5-[6-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl[5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl5-[5-(2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl-[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl[5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl5-[5-((2,2,4,4-tetramethylthiochroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylthiochroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylthiochroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylthiochroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl 6-[(2,2-diethyl-4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate;and

ethyl 6-[2,2-diethyl-4,4,7-trimethylthiochroman-6-yl)ethynyl]nicotinate.

Phenyl 3,3-dimethylacrylate (Compound 37)

To an ice bath cooled solution of 1.29 g (54 mmol) of NaH (obtained froma 60% suspension in mineral oil by 3×10 ml hexane wash) in 20 ml of dryTHF was added slowly under oxygen a solution of 5 g (53 mmol) of phenolin 50 ml of dry THF. The mixture was then treated with a solution of 7 g(59 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The coolingbath was then removed and the mixture was stirred for a further 2.5 h.The reaction mixture was then poured into 150 ml of water containing 1ml of glacial acetic acid. The mixture was extracted with 150 ml etherand the ether extract washed with saturated NaCl solution and then dried(MgSO₄). The solvent was removed in vacuo and the residue purified byflash chromatography (silica; 5% ether in hexanes) to give the titlecompound as a yellow oil. PMR (CDCl₃)): & 1.99 (3H, s), 2.24 (3H, s),5.93 (1H, broad s), 7.10 (2H, d, J-7.8 Hz) 7.22 (1H, t, J-7.8 Hz), 7.38(2H, t, J-7.8 Hz).

4,4-Dimethyl-2-oxo-chroman (Compound 38)

To a stirred, ice-cooled suspension of 10.4 g (78 mmol) of aluminumchloride in 160 ml of methylene chloride was added slowly under argon asolution of 7 g (39.8 mmol) of phenyl 3,3-dimethylacrylate (Compound 37)in 40 ml of methylene chloride. The cooling bath was removed and themixture stirred for a further 42 h. The mixture was poured into amixture of ice and brine and the organic layer separated. The aqueouslayer was extracted with methylene chloride and the organic extractswere combined and washed with saturated NaCl solution and then dried(MgSO₄). The solvent was removed in vacuo and the residue purified byflash chromatography (silica; 10% ether in hexane) to give the titlecompound as a colorless oil. PMR (CDCl₃ : & 1.30 (6H, s), 2.56 (2H, s),7.06 (1H, dd, J-8.0 Hz, 1.4 Hz), 7.16 (1H, td, J-8.0 Hz, 1.4 Hz), 7.26(1H, td, J-8.0 Hz, 1.7 Hz), 7.33 (1H, dd, J-8.0 Hz, 1.7 Hz). MS exactmass, m/e 176.0852 (calcd. for C₁₁ H₁₂ O₂, 176.0837.

2-(1,1,3-Trimethyl-3-hydroxybutyl)phenol (Compound 39)

To 11 ml of 3.0M (33 mmol) methyl magnesium chloride in THF, cooled inan ice bath, was added, under nitrogen, a solution of 1.96 g (11.1 mmol)of 4,4-dimethyl-2-oxo-chroman (Compound 38) in 35 ml of dry ether. Thecooling bath was then removed and the mixture stirred at roomtemperature for 72 h. The reaction mixture was then poured onto amixture of 100 g of ice and 3 ml of conc. H₂ SO₄ and stirred until themagnesium salts were dissolved. The organic layer was separated and theaqueous layer extracted with 2×50 ml of ether. The organic layers werecombined and washed successively with water, saturated NaHCO₃ andsaturated NaCl solutions and then dried (MgSO₄). The solvent was removedin vacuo and the residue was purified by flash chromatography (silica;20% ethyl acetate in hexanes) to give the title compound as a paleyellow solid. PMR (CDCl₃): & 1.13 (6H, s), 1.48 (6H, s), 1.89 (1H, s),2.23 (2H, s), 6.60 (1H, dd, J-7.9 Hz, 1.4 Hz), 6.83 (1H, s), 6..84 (1H,td, J-7.9 Hz, 1.4 Hz), 7.07 (1H, td, J-7.9 Hz, 1.6 Hz), 7.31 (1H, dd,J-7.9 Hz, 1.6 Hz). MS exact mass, m/e 208.1458 (calcd. for C₁₃ H₂₀ O₂,208.1464).

2.2.4,4-Tetramethyl-chroman (Compound 40)

A mixture of 2.98 g (14.3 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl)phenol (Compound 39) and 40 ml of 20% aqueous H₂ SO₄ was heated atreflux, under nitrogen, for 4 h. The mixture was stirred at roomtemperature for a further 72 h and then diluted with 50 ml of water. Themixture was extracted with 3×20 ml of hexanes. The organic extracts werethen combined and washed successively with water and saturated NaClsolution and then dried (MgSO₄). The solvent was then removed in vacuoto give the title compound as a colorless oil. PMR (CDCl₃): & 1.36 (6H,s), 1.37 (6H, s), 1.83 (2H, s), 6.71 (1H, dd, J-8.2 Hz, 1.5 Hz) 6.92(1H, td, J-8.2 Hz, 1.5 Hz), 7.09 (1H, td, J-8.2 Hz, 1.5 Hz), 7.29 (1 H,dd, J-8.2 Hz, 1.5 Hz).

2,2,4,4-Tetramethyl-6-acetyl-chroman (Compound 41)

To an ice bath cooled solution of 2 g (10.53 mmol) of2,2,4,4-tetramethylchroman (Compound 40 ) in 25 ml of nitromethane wasadded, under nitrogen, 941 mg (11.99 mmol) of acetyl chloride followedby 1.59 g (11.92) mmol) of aluminum chloride. The cooling bath was thenremoved and the mixture stirred at room temperature for 16 h. Themixture was then cooled again in an ice bath and treated with 25 ml ofconc. HCl. The mixture was then filtered and the residue washed withmethylene chloride. The filtrate was concentrated in vacuo and theresultant residue was purified by flash chromatography (silica; 10%ethyl acetate in hexanes) to give the title compound as a yellow oil.PMR (CDCl₃): & 1.38 (6H, s), 1.39 (6H, s), 1.87 (2H, s), 2.56 (3H, s),6.83 (1H, d, J-8.7 Hz), 7.71 (1H, dd, J-8.7 Hz, 2.1 Hz), 7.98 (1H, d,J-2.1 Hz). MS exact mass, m/e 232.1468 (calcd. for C₁₃ H₂₀ O₂,232.1464).

2,2,4,4-Tetramethyl-6-ethynyl-chroman (Compound 42)

To a cooled (-78 degrees C.) solution of 522 mg (5.17 mmol) ofdiisopropylamine in 8 ml of dry THF was added slowly, under nitrogen,3.23 ml of 1.6M (5.17 mmol) n-butyl lithium in hexane. The mixture wasstirred at -78 degrees C. for 40 minutes and then treated with asolution of 1.24 g (5.17 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman(Compound 41) in 2 ml of dry THF. The mixture was stirred at -78 degreesC. for a further 1 h and then treated with 895 mg (5.19 mmol) ofdiethylchlorophosphate. The reaction mixture was allowed to warm to roomtemperature and transferred by double-ended needle into a solution oflithium diisopropylamide in THF at -78 degrees C. [prepared as describedabove from 1.04 g (10.34 mmol) of diisopropylamine and 6.46 ml of 1.6M(10.34 mmol) n-butyl lithium in hexane]. The cooling bath was removedand the mixture was stirred at room temperature for 16 h. The mixturewas then treated with 10 ml of ice water and acidified to a pH of 2 with10% HCl. The organic layer was separated and the aqueous layer wasextracted with 3×30 ml of pentane. The organic extracts were combinedand washed successively with 2×30 ml of dilute HCl, water, 3×30 ml ofsaturated NaHCO₃ solution and saturated NaCl solution and then dried(MgSO₄). The solvent was removed in vacuo and the residue was purifiedby flash chromatography (silica; 2% ethyl acetate in hexane) to give thetitle compound as a pale yellow oil. PMR (CDCl₃): & 1.31 (6H, s), 1.32(6H, s), 1.50 (2H, s), 3.00 (1H, s), 6.72 (1H, d, J-8.4 Hz), 7.20 (1H,dd, J-8.4 Hz, 2.1 Hz), 7.42 (1H, d, J-2.1 Hz). MS exact mass, m/e214.1251 (calcd. for C₁₅ H₁₈ O, 214.1357).

Ethyl 6-[(2,2,4,4-tetramethylchroman-6-yl)-ethynyl]nicotinate (Compound3)

A solution of 233 mg (1.09 mmol) of 2,2,4,4-tetramethyl-6-ethynylchroman(Compound 42) and 209 mg (1.09 mmol) of ethyl 6-chloronicotinate(Compound 29) in 1 ml of triethylamine was degassed and then treatedunder argon with a powdered mixture of 50 mg (0.26 mmol) of cuprousiodide and 100 mg (0.14 mmol) of bis(triphenylphosphine) palladium (II)chloride. The reaction mixture was heated under argon at 55 degrees C.for 80 h and then cooled to room temperature. The triethylamine was thenremoved under vacuum and the residue purified by flash chromatography(silica; 5% ethyl acetate in hexanes) to give the title compound as ayellow oil. PMR (CDCl₃): & 1.36 (12H, s), 1.42 (3H, t, J-7.2 Hz), 1.85(2H, s), 4.37 (2H, q, J-7.2 Hz), 6.79 (1H, d, J-0.4 Hz), 7.34 (1H, dd,J-8.4 Hz, 2.1 Hz), 7.56 (1H, d, J-8.7 Hz), 7.60 (1H, d, J-2.1 Hz), 8.27(1H, dd, J-8.7 Hz, 2.4 Hz), 9.19 (1H, d, J-2.4 Hz). MS exact masss, m/e363.1837 (calcd. for C₂₃ H₂₅ O₃ N, 363.1834).

3-Methyl-phenyl-3,3-dimethylacrylate (Compound 44)

A 60% suspension of sodium hydride (3.22 g; 81 mmol) in mineral oil waswashed with 3×10 ml of hexane and then treated with 30 ml of dry THF.This mixture was cooled in an ice-bath and then treated with a solutionof 8.6 g (79.5 mmol) of m-cresol in 80 ml of dry THF. The reactionmixture was stirred for 10 min and then treated with a solution of 10.5g (88.5 mmol) of dimethylacryloyl chloride in 40 ml of dry THF. Thereaction mixture was stirred at room temperature for 96 h and thenpoured into a mixture of 150 ml of water and 1 ml of glacial aceticacid. The mixture was stirred for 10 min and the organic layer wasseparated. The aqueous layer was extracted with 2×50 ml of ether. Theorganic layers were combined and washed successively with water andsaturated NaCl solution and then dried (MgSO₄). The solvent was removedin vacuo and the residue was purified by flash chromatography (silica;10% ethyl acetate in hexane) to give the title compound as a pale yellowoil. PMR (CDCl₃): & 1.95 (3H, d, J-1.3 Hz), 2.21 (3H, d, J-1.2 Hz), 2.34(3H, s), 5.90 (1H, broad S), 6.86-6.93 (2H, m), 7.01 (1H, d, J-7.2 Hz),7.24 (1H, t, J-7.2 Hz).

2-(1,1,3-Trimethyl-3-hydroxybutyl) 5-methyl-phenol (Compound 45)

To an ice-bath cooled suspension of 13 g (97.5 mmol) of aluminumchloride in 200 ml of methylene chloride was added dropwise under argona solution of 9.0 g (47.4 mmol) of 3-methyl-phenyl-3,3-dimethylacrylate(Compound 44) in 100 ml of methylene chloride. The reaction mixture wasstirred at 0 degrees C. for a further 30 min and then at roomtemperature for 15 h. The reaction mixture was poured into 200 ml of anice water/salt mixture and the organic layer was separated. The aqueouslayer was extracted with 50 ml of ether. The organic layers werecombined and washed successively with water and saturated NaCl solutionand then dried (MgSO₄). The solvent was removed in vacuo and the residuepurified by flash chromatography (silica; 5% ethyl acetate in hexane) togive an approximately 2.5:1 mixture of isomeric products,4,4,7-trimethyl-2-oxo-chroman and 4,4,5-trimethyl-2-oxo-chroman as apale yellow oil. To a solution of 3.8 g (20 mmol) of this mixture ofisomeric 2-oxo-chromans in 60 ml of ether at 0 degrees C. was addedunder argon 20 ml of 3.0M (60 mmol) of methyl magnesium bromide inether. The reaction mixture was stirred at room temperature for 48 h andthen poured onto a mixture of ice and 1 ml of conc. H₂ SO₄. The organiclayer was separated and the aqueous layer extracted with 2×50 ml ofether. The organic layers were combined and washed successively withwater, saturated NaHCO₃ solution, water again and then saturated NcClsolution and then dried (MgSO₄). The solvent was removed in vacuo andthe residue was purified by flash chromatography (silica; 15% ethylacetate in hexanes) to give the title compound as a colorless oil. PMR(CDCl₃): & 1.14 (6H, s), 1.45 (6H, s), 2.19 (3H, s), 2.21 (2H, s), 6.39(1H, d, J-1.8 Hz), 6.67 (1H, dd, J-7.9 Hz, 1.8 Hz), 7.16 (1H, d, J-7.9Hz), 7.44 (1H, s).

2,2,4,4,7-Pentamethyl-chroman (Compound 46)

To 2.16 g (11.7 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl)5-methyl-phenol (Compound 45) was added under nitrogen 50 ml of 20%aqueous sulfuric acid. The reaction mixture was heated at reflux for 13h and then cooled. The organic layer was separated and the aqueous layerwas extracted with ether. The organic extracts were combined and washedsuccessively with water, saturated NaHCO₃ solution, water again andsaturated NaCl solution and then dried (MgSO₄). The solvent was removedin vacuo to give the title compound as a yellow oil. PMR (CDCl₃): & 1.32(6H, s), 1.34 (6H, s), 1.81 (2H, s), 2.26 (3H, s), 6.63 (1H, s), 6.72(1H, d, J-7.9 Hz), 7.15 (1H, d, J-7.9 Hz).

2,2,4,4,7-Pentamethyl-6-acetyl-chroman (Compound 47)

To an ice-bath cooled solution of 1.96 g (9.6 mmol) of2,2,4,4,7-pentamethyl-chroman (Compound 46) in 30 ml of nitromethane wasadded under argon 1.059 g (13.5 mmol) of acetyl chloride followed by 1.9g (14.3 mmol) of aluminum chloride. The reaction mixture was stirred atroom temperature for 14 h and then cooled in an ice-bath and treatedwith 25 ml of conc. HCl. The mixture was warmed to room temperature anddiluted with ether and water. The organic layer was separated and theaqueous layer extracted with ether. The organic extracts were combinedand washed successively with water, saturated NaHCO₃ solution, wateragain, and saturated NaCl solution, and then dried (MgSO₄). The solventwas removed in vacuo and the residue was purified by flashchromatography (silica; 5% ethyl acetate in hexanes) to give the titlecompound as a pale yellow oil. PMR (CDCl₃): & 1.36 (6H, s), 1.37 (6H,s), 1.86 (2H, s), 2.49 (3H, s), 2.56 (3H, s), 6.65 (1H, s), 7.74 (1H,s).

2,2,4,4,7-Pentamethyl-6-ethynyl-chroman (Compound 48)

To a solution of 455 mg (4.5 mmol) of disopropylamine in 5 ml of dry THFat -78 degrees C. was added under argon 3 ml of 1.5M n-BuLi in hexane.The mixture was stirred at -78 degrees C. for a further 45 min and thentreated with a solution of 1.07 g (4.3 mmol) of2,2,4,4,7-pentamethyl-6-acetyl-chroman (Compound 47) in 4 ml of dry THF.The reaction mixture was stirred at -78 degrees C. for 1 h and thentreated with 776 mg (4.5 mmol) of diethyl chlorophosphate. The mixturewas allowed to warm to room temperature and then transferred by adouble-ended needle into a solution of lithium diisopropyl amide in 10ml dry THF at -78 degrees C. which was prepared as described above using910 mg (9.0 mmol) of diisopropylamine and 6 ml of 1.5M (9.0 mmol) n-BuLiin hexane. The mixture was stirred at room temperature fur 15 h and thenpoured into 10 ml of iced water. The mixture was acidified to pH=2 with10% HCl solution. The organic layer was separated and the aqueous layerextracted with pentane. The organic extracts were combined and washedsuccessively with water, saturated NaHCO₃ and saturated NaCl solutionsand then dried (MgSO₄). The solvent was removed in vacuo and the residuepurified by Kugelrohr distillation (82 degrees C., 0.3 mm) to give thetitle compound as a pale yellow oil. PHR (CDCl₃): & 1.32 (6H, s), 1.34(6H, s), 1.81 (2H, s), 2.36 (3H, s), 3.18 (1H, s), 6.64 (1H, s), 7.40 1H(s). MS exact mass, m/e 228.1520 (calcd. for C₁₆ H₂₀ O, 228.1514).

Ethyl-6-[(2,2,4,4,7-pentamethyl-6-chromanyl)-ethynyl] nicotinate(Compound 7)

A solution of 300 mg (1.316 mmol) of2,2,4,4,7-pentamethyl-6-ethynyl-chroman (Compound 48) and 245.6 mg(1.3276 mmol) of ethyl 6-chloro-nicotinate (Compound 29) in 2 ml oftriethylamine was placed in a pressure tube and a stream of nitrogen wasbubbled through the solution for 15 min. The tube was then flushed withargon and a finely ground mixture of 100 mg (0.1425 mmol) of bis(triphenylphosphine) palladium (II) chloride and 50 mg (0.2625 mmol) ofcuprous iodide was added to the solution. The pressure tube was thensealed and the reaction mixture heated at 60 degrees C. for 72 h. Themixture was cooled to room temperature and the triethylamine removedunder vacuum. The residue was purified by flash chromatography (silica;10% ethyl acetate in hexane) to give the title compound as a yellowsolid. PMR (CDCl₃): & 1.37 (6H, s), 1.38 (6H, s), 1.44 (3H, t, J-7.2Hz), 1.85 (2H, s), 2.49 (3H, s), 4.43 (2H, q, J-7.2 Hz), 6.70 (1H, s),7.55-7.61 (2H, m), 8.28 (1H, dd, J-8.2 Hz, 2.1 Hz), 9.22 (1H, d, J-2.1Hz). MS exact mass, m/e 377.1982 (calcd. for C₂₄ H₂₇ O₃ N, 377.1991).

2-[2,2(4,4-tetramethylchroman-6-yl)ethynyl]-5-hydroxymethylpyridine(Compound 50)

A 250 ml 3-necked flask is fitted with a stirrer, a dropping funnel, anitrogen inlet and a thermometer. In the flask 1is placed a solution of379.5 mg (10 mmol) of lithium aluminum hydride in 30 ml of dry diethylether. The solution is cooled to -65 degrees C. under nitrogen and asolution of 3.632 g (10 mmol) of ethyl6-[(2,2,4,4-tetramethylchroman-6-yl)ethynyl]nicotinate (Compound 43) in15 ml of dry ether is added dropwise at a rate such that the temperaturedoes not exceed -60 degrees C. The mixture is stirred at -30 degrees C.for 1 hour and the excess hydride is then destroyed by the addition of300 mg (3.4 mmol) of ethyl acetate. The reaction mixture is thenhydrolyzed by adding 3 ml of saturated ammonium chloride solution andallowing the temperature to rise to room temperature. The mixture isthen filtered and the residue washed with ether. The ether layer is thenwashed with saturated solium chloride solution, dried (MgSO₄) and thenconcentrated in vacuo. The residue is purified by chromatograhy followedby recrystallization to give the title compound.

By the same process, acids or esters of this invention may be convertedto their corresponding primary alcohols.

2-[2,2,4,4-tetramethylchroman-6-yl)ethynyl]-5-acetoxymethylpyridine(Compound 51)

A solution of 3.09 g (10 mmol) of2,2,4,4-tetramethyl-6-[2-(5-hydroxymethylpyrid-2-yl)ethynyl]chroman(Compound 50) 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol)of dicyclohexylcarbodiimide and 460 mg (3.765 mmol) of4-dimethylaminopyridine in 150 ml methylene chloride is stirred at roomtemperature for 48 hours. The reaction mixture is then filtered and theresidue washed with 50 ml of methlene chloride. The filtrate is thenconcentrated in vacuo and the residue is purified by chromatographyfollowed by recrystallization to give the title compound.

Proceeding in the same manner, other alcohols of this invention may beesterified.

2-[(2,2,4,4-tetramethylchroman-6-yl)ethynyl]-pyridine-5-carboxaldehyde(Compound 52)

A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in25 ml of methylene chloride is placed in a 4-necked flask equipped witha stirrer, a thermometer and two pressure-equalizing addition funnelsfitted with drying tubes. The solution is cooled to -60 degrees C. andthen treated dropwise with a solution of 1.875 g (24 mmol) of dimethylsulfoxide (distilled from calcium hydride) in 5 ml of methylene chlorideover a five minute period. The reaction mixture is then stirred at -60degrees C. for an additional 10 minutes. A solution of 3.10 g (10 mmol)of 2,2,4,4-tetramethyl-6-[(5-hydroxymethylpyrid-2-yl)ethynyl]-chroman(Compound 50) in 10 ml of methylene chloride is then added to thereaction mixture over a period of 5 minutes. The mixture is stirred fora further 15 minutes and is then treated with 5.06 g (50 mmol) oftriethylamine. The cooling bath is then removed and the mixture isallowed to warm to room temperature. Thirty ml of water is then added tothe mixture and stirring is continued for a further 10 minutes. Theorganic layer is then separated and the aqueous layer is extracted with20 ml of methylene chloride. The organic layers are then combined andwashed successively with dilute HCl, water and dilute Na₂ CO₃ solutionand then dried (MgSO₄). The solution is then filtered and concentratedin vacuo and the residue is purified by chromatography followed byrecrystallization to give the title compound.

Primary alcohols of this invention may be oxidized to theircorresponding aldehydes by this method.

2-[(2,2,4,4-tetramethylchroman-6-yl)ethynyl]-5-(1-hydroxyropyl)pyridine(Compound 53)

Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether isplaced in a 3-necked flask fitted with a mechanical stirrer, a refluxcondenser protected by a drying tube and a pressure-equalizing droppingfunnel protected by a drying tube. The flask is cooled in an ice bathand a solution of 2.98 g (10 mmol) of2-[2,2,4,4-tetramethylchroman-6-yl) ethynyl]-pryidine-5-carboxaldehyde(Compoound 52) in 10 ml of dry ether is added slowly with vigorousstirring. The cooling bath is then removed and the mixture heated atreflux for 3 hours. The mixture is then cooled in an ice-salt bath and 5ml of saturated ammonium chloride solution added. The mixture is stirredfor a further 1 hour and then filtered and the residue washed with two10 ml portions of ether. The ether solution is then separated, dried(MgSO₄) and the ether removed in vacuo. The residue is then purified bychromatography followed by recrystallization to tive the title compound.

Using the same procedure any of the other aldehydes of this inventioncan be converted to the corresponding secondary alcohols.

Such secondary alcohols may be converted to their corresponding ketonesusing the procedure described for the preparation of Compound 52 orother oxidation procedures.

2-[(2,2,4,4-tetramethylchroman-6-yl)ethynyl]-5-dimethoxymethylpyridine(Compound 54)

A round-bottomed flask is fitted with a Dean-Stark apparatus under areflux condenser protected by a drying tube. A mixture of 3.58 g (12mmol) of2-[2,2,4,4-tetramethyl-chroman-6-yl)-ethynyl]-pyridine-5-carboxaldehyde(Compound 52) 4.80 mg (15 mmol) of anhydrous methanol, 2 mg ofp-toluenesulfonic acid monohydrate and 10 ml of anhydrous benzene isplaced in the flask and the mixture heated at reflux under nitrogenuntil close to the theoretical amount of water is collected in theDean-Stark trap. The reaction mixture is cooled to room temperature andextracted successively with 5 ml of 10% sodium hydroxide solution andtwo 5 ml portions of water and then dried (MgSO₄). The solution is thenfiltered and the solvent removed in vacuo. The residue is purified bychromatography and then recrystallization to give the title compound.

In a similar manner, any aldehyde or ketone of this invention may beconverted to an acetal or a ketal.

Following the procedures set forth above, with such modificiation whichwill be readily apparent to a synthetic organic chemist of ordinaryskill in light of the present disclosure, the following further examplesof compounds can be prepared:

2,2,4,4-tetramethyl-6-acetyl-7-ethylchroman;

2,2,4,4-tetramethyl-6-acetyl-7-propylchroman;

2,2,4,4-tetramethyl-6-acetyl-7-butylchroman;

2,2,4,4-tetramethyl-6-acetyl-7-pentylchroman;

2,2,4,4-tetramethyl-6-acetyl-7-hexylchroman;

2,2-diethyl-4,4-dimethyl-6-acetyl-chroman;

2,2-diethyl,-4,4,7-trimethyl-6-acetyl-chroman;

ethyl 6-[(2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl]nicotinate;

ethyl 6-[(2,2,4,4-tetramethyl-7-propylchroman-6-yl)ethynyl]nicotinate;

ethyl 6-[(2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl]nicotinate;

ethyl [2-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl [2-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl[2-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl[2-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrid-5-yl]acetate;

ethyl3-[2-((2,2,4,.4-tetramethylchroman-2-yl)ethynyl)pyrid-5-yl]propionate;

ethyl3-[2-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl)pyrid-5-yl]propionate;

ethyl3-[2((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrid-5-yl]propionate;

ethyl3-[2((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrid-5-yl]propionate;

ethyl5-[2-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl5-[2-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl5-[2-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrid-5-yl]pentanoate;

ethyl5-[2-((2,2,4,4-tetramethylchroman-6-yl-ethynyl)pyrid-5-yl]pentanoate;

ethyl 5-[2-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)-fur-2-yl]acetate

ethyl [5-((2,2,3,3,7-pentamethylchroman-6-yl)ethynyl)fur-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)fur-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl-fur-2-yl]acetate;

ethyl5-[5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)fur-2-yl]pentanoate;

ethyl [5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl [5-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl [5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)thien-2-yl]acetate;

ethyl5-[5((2,2,4,4-tetramethylchroman-6-yl)ethynyl)thien-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl)thien-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)thien-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)thien-2-yl]pentanoate;

ethyl[6-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl[6-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl[6-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl[6-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyridazin-3-yl]acetate;

ethyl5-[6-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl5-[6-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl)pyridazin-3-yl]pentanoate;

ethyl5-[6-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl5-[6-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyridazin-3-yl]pentanoate;

ethyl[5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl[5-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrimidin-2-yl]acetate;

ethyl5-[5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl)pyrimidin-2-yl]pentanoate;

ethyl5-[4-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrimidin-2-yl]pentanoate;

ethyl [5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-((2,2,4,4,7-pentamethylchroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrazin-2-yl]acetate;

ethyl[5-[5-((2,2,4,4-tetramethylchroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4,7-pentamethylchroman-6-yl)-ethynyl)pyrazin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-ethylchroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl5-[5-((2,2,4,4-tetramethyl-7-hexylchroman-6-yl)ethynyl)pyrazin-2-yl]pentanoate;

ethyl 6-[2,2-diethyl-4,4-dimethylchroman-6-yl)ethynyl] nicotinate; and

ethyl 6-[2,2-diethyl-4,4,7-trimethylchroman-6-yl)ethynyl] nicotinate.

EXAMPLES OF FORMULATION FOR TOPICAL ADMINISTRATION

Preferably the compounds of the invention may be administered topicallyusing various formulations. Such formulations may be as follows:

    ______________________________________                                        Ingredient          Weight/Percent                                            ______________________________________                                        Solution                                                                      Retinoid (active ingredient)                                                                      0.1                                                       BHT                 0.1                                                       Alcohol USP         58.0                                                      Polyesthylene Glycol 400 NF                                                                       41.8                                                      Gel                                                                           Retinoid (active ingredient)                                                                      0.1                                                       BHT                 0.1                                                       Alcohol USP         97.8                                                      Hydroxypropyl Cellulose                                                                           2.0                                                       ______________________________________                                    

What is claimed is:
 1. Compounds of the formula ##STR9## where X is S,O, or NR', where R' is hydrogen or lower alkyl;R₁, R₂ and R₃ arehydrogen or lower alkyl; R₄ and R₅ are hydrogen or lower alkyl with theproviso that R₄ and R₅ both are not hydrogen; n is an integer from 0 to5; A is selected from a group consisting of pyrimidinyl, and B ishydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈,COONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O,--COR", CR"(OR₁₂)₂, or CR"OR₁₃ O, where R" is an alkyl, cycloalkyl oralkenyl group having 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl orlower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl groupof 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenylor lower alkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl,R₁₂ is lower alkyl, R₁₃ is divalent alkyl radical of 2-5 carbons. 2.Compounds of claim 1 where X is S.
 3. Compounds of claim 2 where n is 0,1, or
 2. 4. Compounds of claim 3 where n is O.
 5. Compounds of claim 3where B is COOH or a pharmaceutically acceptable salt thereof, COOR₈ orCOONR₉ R₁₀.
 6. Compounds of claim 3 where R₃ is hydrogen or methyl. 7.Compounds of claim 3 where R₄ is the same alkyl group as R₅. 8.Compounds of claim 1 where X is O.
 9. Compounds of claim 8 where n is 0,1 or
 2. 10. Compounds of claim 9 where n is O.
 11. Compounds of claim 9where B is COOH or a pharmaceutically acceptable salt thereof, COOR₈ orCOONR₉ R₁₀.
 12. Compounds of claim 9 where R₃ is hydrogen or methyl. 13.Compounds of claim 9 where R₄ is the same alkyl group as R₅.
 14. Apharmaceutical composition comprising one or more compounds set forth inclaim 1 in an amount effective for treating the conditions selected fromacne, Darier's disease, psoriasis, icthyosis, excema, atopic dermatitis,epithelial cancer, immunological disorders, dry eye syndrome and forpromoting wound healing and reversing effects of sun damage to skin, thecomposition including a pharmaceutically acceptable excipient.
 15. Apharmaceutical composition as set forth in claim 14, said compositioncontaining an effective amount of one or more compounds set forth inclaim 14, the composition being useful for treating skin disordersselected from acne, Darier's disease, psoriasis, icthyosis, excema,atopic dermatitis, and epithelial cancer in a mammal.